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Novel thiazolidinedione derivatives of the potent antioxidant, alpha-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-[4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy]ethyl)-5-(1,2-dithiolan-3-yl)- N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARgamma) (EC(50) range 15-101 nM) and modest activators of PPARalpha (EC(50) 5 microM). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.

Purpose: It is postulated that an anterior anal fissure can result from mucosal trauma occurring during distention of a rectocele and that repair of the rectocele by anterior levatorplasty can lead to healing of these anal fissures. This study was designed to compare anterior levatorplasty with internal sphincterotomy for the management of anterior anal fissures in females with a rectocele., Methods: From June 2000 until May 2002, 54 consecutive females with an anterior anal fissure and a rectocele were randomized to be managed by internal sphincterotomy or anterior levatorplasty. Preoperatively, manometry was performed, continence was measured using the Cleveland Clinic scoring system, pain scores were obtained using a visual analog scale, and the symptoms of bleeding and straining to defecate were assessed. Postoperatively, pain scores were obtained at Days 2, 7, and 21. Manometry, continence scores, and resolution of symptoms were measured between 8 and 12 weeks. Patient satisfaction and fissure healing also were assessed between 8 and 12 weeks. The average length of follow-up was 20 (range, 6-30) months., Results: Postoperatively, lateral sphincterotomy caused a decrease in the resting pressures and anterior levatorplasty resulted in an increased length of the anal canal. Anterior levatorplasty also caused increased postoperative pain scores. There were no differences in fissure healing and patient satisfaction., Conclusions: These data suggest that anterior levatorplasty is an option for the management of patients with a rectocele, which may avoid the risk of incontinence with lateral internal sphincterotomy and better address the etiology of anterior anal fissures.

The main recommendations for the use of ciclosporin in the management of psoriasis are: (i) intermittent short courses (average of 12 weeks duration) of ciclosporin are preferable; (ii) ciclosporin should be given in the dose range 2.5-5.0 mg kg(-1) day(-1) (doses greater than 5.0 mg kg(-1) day(-1) should only be given in exceptional circumstances); (iii) treatment regimens should be tailored to the needs of each patient; (iv) selection of patients should take into account psychosocial disability, as well as clinical extent of disease and failure of previous treatment; (v) each patient's renal function (as measured by serum creatinine) should be thoroughly assessed before and during treatment; (vi) each patient's blood pressure should be carefully monitored before and during treatment; (vii) adherence to treatment guidelines substantially reduces the risk of adverse events; (viii) long-term continuous ciclosporin therapy may be appropriate in a subgroup of patients; however, duration of treatment should be kept below 2 years whenever possible; and (ix) when long-term continuous ciclosporin therapy is necessary, annual evaluation of glomerular filtration rate may be useful to accurately monitor renal function.

Purpose: This report describes a treatment method for patients with persistent anastomostic sinuses in which fibrin glue is used., Methods: A retrospective review was conducted of the medical records of seven patients with radiologically documented sinus tracts after restorative proctocolectomy or low rectal anastomosis was managed with fibrin glue obliteration of the tract. The sinus was gently debrided with a curette and then filled with fibrin glue. Postoperatively, the patients received metronidazole 1.5 g per day in divided doses for one week. Outpatient examination of the internal opening was performed at 1, 3, and 12 weeks postoperatively., Results: In all patients, healing of the sinus was observed after one week. After an average of 11.2 months (range, 3-15) of follow-up there were no recurrences and no episodes of pelvic sepsis., Conclusion: On the basis of this experience, we believe that fibrin glue injection may be an alternative method of managing pelvic anastomotic sinuses.

This study was undertaken to evaluate the effects of thiazolidinediones (TZD) on keratinocyte proliferation, motility, and matrix metalloproteinase (MMP) production. Rosiglitazone (a potent TZD) inhibited both proliferation and motility as well as elaboration of MMP-1 and MMP-9. Inhibition was obtained with keratinocytes in monolayer culture and human skin in organ culture. There were significant concentration-response differences in sensitivity of the three keratinocyte responses to treatment with rosiglitazone. In contrast to keratinocytes, dermal fibroblasts were resistant to the effects of rosiglitazone. Treatment of keratinocytes with rosiglitazone did not suppress epidermal growth factor receptor autophosphorylation, but inhibited signaling through the extracellular regulated kinase mitogen-activated protein kinase pathway without a concomitant effect on pathways that lead to c-jun activation. Pioglitazone, another TZD, also suppressed keratinocyte proliferation, although it was less effective than rosiglitazone. An experimental TZD (BP-1107) inhibited keratinocyte proliferation at a much lower concentration than either rosiglitazone or pioglitazone. Because enhanced keratinocyte motility and increased MMP production as well as increased keratinocyte proliferation are thought to contribute to the phenotype of psoriatic lesional skin, we propose that interference with these keratinocyte responses contributes to the previously reported antipsoriatic activity of TZD.

Background: Few cost-effectiveness analyses have been conducted on topical therapies for atopic dermatitis., Objective: We sought to compare cost-effectiveness of high-potency topical corticosteroids (HPTCs) and tacrolimus ointment for the treatment of moderate to severe atopic dermatitis for patients who are not responsive to or not well controlled with mid-potency topical corticosteroids., Methods: A Markov model represented the cyclic nature of atopic dermatitis. Clinical outcomes were derived from published literature. "Efficacy" was defined as disease-controlled days on which patients experienced a greater than 75% improvement in their disease. Resource use and changes in management were on the basis of opinions of a physician panel; secondary treatment was an oral antibiotic with topical corticosteroids. Sensitivity analyses were conducted for all variables., Results: The model was sensitive to duration of continuous treatment with HPTCs. HPTCs, when limited to 2-week treatment cycles, were associated with the highest total costs ($1682 per year) and the least efficacy (185 disease-controlled days). HPTCs in 4-week treatment intervals and tacrolimus ointment were similar in total costs and efficacy ($1317 vs $1323 for 194 vs 190 disease-controlled days, respectively). Although primary drug costs were higher for patients treated with tacrolimus ointment, patients treated with regimens of HPTCs incurred higher secondary drug costs., Conclusion: In the base case analyses, tacrolimus ointment was more cost-effective than HPTCs administered in 2-week treatment cycles, and similar in cost-effectiveness to 4-week cycles of HPTCs.

Background: Alefacept, human LFA-3/IgG1 fusion protein, is a novel biological agent currently being developed for the treatment of chronic plaque psoriasis. Alefacept selectively reduces the memory-effector T cells that have been implicated in the pathogenesis of the disease; as a result, alefacept is classified as a therapy that induces remission (so-called 'remittive' therapy). In a previously published randomized, placebo-controlled phase II study of intravenous alefacept in 229 patients with chronic plaque psoriasis, clinical improvement was observed during dosing as well as in the postdosing follow-up period., Objectives: To assess the remission period following alefacept therapy., Methods: The time before re-treatment was required was measured in patients who were 'clear' or 'almost clear' of disease according to a physician global assessment at the end of the follow-up phase., Results: In these patients, responses were sustained for a median of 10 months, and for up to 18 months. No patient reported disease rebound after cessation of alefacept., Conclusions: Alefacept is a biological agent for the treatment of chronic plaque psoriasis that provides disease-free intervals and time off drug therapy.

Background: Psoriasis is a chronic, relapsing skin disease that may require multiple treatment courses. Alefacept targets the memory T cells implicated in psoriasis pathogenesis. This open-label study evaluated the safety and tolerability, efficacy, and pharmacodynamics of repeat courses of alefacept in men and women with chronic plaque psoriasis. This article reports the interim results of this ongoing study., Methods: Patients (n = 174) who participated in previous phase II studies of alefacept were included in this retreatment study. Intravenous alefacept (7.5 mg) was administered once weekly for 12 weeks followed by 12 weeks of observation. Initial and subsequent retreatment courses were only given when, in the opinion of the investigators, disease had returned and necessitated treatment; CD4+ T-cell counts had to be at or above the lower limit of normal., Results: Adverse events were similar regardless of the retreatment course. No opportunistic infections, rebound of disease, or flares were reported. Low titers of anti-alefacept antibodies occurred in a few patients without related safety issues. Sixty-six per cent of patients achieved a >/= 50% reduction in the Psoriasis Area and Severity Index (PASI) at any time after the first dose of retreatment course 1. Patients who received two retreatment courses (n = 50) had consistent or improved responses after the second course; 64% and 68% of these patients achieved a >/= 50% PASI improvement at any time after the first dose of retreatment courses 1 and 2, respectively. Alefacept selectively reduced memory T cells without cumulative effects., Conclusions: Repeat courses of alefacept were well tolerated, and subsequent retreatment courses were at least as effective as the initial course of therapy.

Introduction: Chronic plaque psoriasis has a profound impact on patient quality of life (QOL), including adverse psychosocial effects, impaired daily activities, anxiety, and depression., Objective: To assess health-related QOL in a randomized phase II trial of alefacept (human LFA-3/IgG(1) fusion protein), a selective immunomodulator for psoriasis., Study Design: Multicenter, randomized, placebo-controlled, double-blind trial., Methods: 229 patients with moderate to severe psoriasis were randomized to alefacept (0.025, 0.075, or 0.150 mg/kg) or placebo by 30-second intravenous bolus once weekly for 12 weeks and followed for 12 additional weeks. Patients completed a general (SF-36) Health Survey) and dermatology-specific (Dermatology Life Quality Index [DLQI] and Dermatology Quality Of Life Scales [DQOLS]) QOL surveys at each study visit., Results: Patients treated with alefacept had significantly greater improvements on dermatology-specific QOL scales compared with patients receiving placebo (p < 0.05). Patients who achieved a >or=50% or a >or=75% reduction in Psoriasis Area and Severity Index (PASI) reported similar improvement in QOL, which was significantly greater than that of other patients., Conclusions: The clinical effect of alefacept on psoriasis is associated with an improvement in patients' QOL. Among patients with moderate to severe psoriasis, an improvement in PASI of 50% or more is associated with better QOL scores.

Background: The use of expert opinion is widespread in economic studies of healthcare utilisation; however, few studies have attempted to assess the validity of assumptions derived from such sources., Objective: To examine the use of such expert opinion in determining comorbidities associated with atopic dermatitis/eczema (AD/E), which were assessed as part of a recent third-party payer cost-of-illness study., Design: To identify the disease-related comorbidities that would represent costs associated with AD/E, physicians on an expert panel were asked individually and then collectively to group all International Classification of Diseases, 9(th) Edition-Clinical Modification (ICD-9-CM) diagnosis codes as 'most likely', 'possibly' or 'definitely not' related to the costs of identifying and treating patients with AD/E. Claims representing $US464 million in payer reimbursements from nearly 125 000 patients with AD/E were identified within two separate claims databases (1997 values). Over 850 ICD-9-CM diagnosis codes were identified in the first-listed position from these claims. For each group of 'most likely', 'possibly' and 'definitely not' related diagnosis codes, prevalence rates were compared within AD/E and non-AD/E populations from the two historical payer claims databases. Adjusted and non-adjusted odds ratios were calculated by comparing prevalence rates between AD/E and non-AD/E patients in the same payer population., Results: The mean prevalence rate of any diagnosis code in the AD/E population was 0.65 +/- 1.82% (SD) with a mean odds ratio of 1.81 +/- 0.96. Comorbidities considered by the expert panel 'most likely' to be associated with AD/E had higher prevalence rates (3.28 +/- 3.63%) and odds ratios (2.14 +/- 1.14). Comorbidities considered to be 'possibly' related to AD/E had prevalence rates and odds ratios of 3.01 +/- 5.06% and 1.84 +/- 0.82, respectively. Comorbidities considered to be 'definitely not' related to AD/E had the lowest prevalence rates (0.45 +/- 1.09%) and odds ratios (1.80 +/- 0.97)., Conclusions: Comparing the result of consensus panels with actual claims histories validated the use of expert opinion in determining comorbidities associated with AD/E. Expert opinion yielded valid results in terms of identifying comorbidities that manifested frequently and disproportionately in the AD/E population. Limited statistical measurements of comorbidities would have been less specific than expert opinion. Future cost-of-illness studies should consider alternative data sources and methodologies to enhance the validity and importance of expert opinion and to corroborate their findings.

Background: In previous phase II studies, alefacept significantly improved psoriasis and was well tolerated. The clinical response to alefacept was durable., Objective: Our purpose was to further evaluate efficacy and tolerability of alefacept in a phase III study of patients (n = 553) with chronic plaque psoriasis., Methods: Two 12-week courses of once-weekly intravenous alefacept 7.5 mg or placebo were given in a randomized double-blind study; patients were followed up for 12 weeks after each course., Results: During treatment and follow-up of course 1, a 75% or greater reduction in the Psoriasis Area Severity Index (PASI) was achieved by 28% of alefacept-treated and 8% of placebo-treated patients (P <.001). Patients who received a single course of alefacept and achieved a 75% or greater reduction from baseline PASI during or after treatment, without the use of phototherapy or systemic therapies, maintained a 50% or greater reduction in PASI for a median duration of more than 7 months. Among patients who received 2 courses of alefacept, 40% and 71% of patients achieved a 75% or greater and 50% or greater reduction in PASI, respectively, during the study period. Alefacept was well tolerated over both courses. In course 1, the incidence of transient chills was higher in the alefacept group compared with the placebo group; more than 90% of cases occurred within 24 hours after the first few doses., Conclusion: Alefacept significantly improved psoriasis and produced durable clinical improvements among patients who responded. A second course of alefacept increased efficacy and was equally well tolerated.

Purpose: Temporary fecal diversion may be desired after many anorectal procedures. The aim of this study was to describe a technique for laparoscopy-assisted creation of a loop ileostomy in patients undergoing anorectal and perineal surgery and to relate short-term outcomes., Methods: A retrospective review of the medical records of 53 consecutive patients who underwent laparoscopy-assisted creation of a loop ileostomy as an adjunct to anorectal or perineal surgery between 1993 and 1999 was performed. Data were obtained for age of the patient, previous abdominal surgical procedures, anorectal or perineal surgical procedure performed, American Society of Anesthesiology scores, operative times for both creation and takedown of the ileostomy, and postoperative return of bowel function., Results: The average duration of operation for laparoscopy-assisted creation of the loop ileostomy was 47 (range, 28-75) minutes, with no conversions to laparotomy. All patients were able to tolerate a regular diet on the first postoperative day. Closure was accomplished 69 (range, 63-96) days later with an average operative time of 52 (range, 35-90) minutes. One patient developed ileus after takedown of his stoma. The other 52 patients were able to tolerate a regular diet by the second postoperative day., Conclusion: Laparoscopy-assisted creation of a loop ileostomy is an effective method for temporary fecal diversion in patients undergoing anorectal surgery.

Sulfasalazine is used as a therapy for various autoimmune conditions, including psoriasis; its effectiveness is presumed to be the result of its immunomodulatory effects. We have treated patients with severe alopecia areata with sulfasalazine as part of our dermatology practice and have noticed cosmetically acceptable regrowth in 23% of patients in whom a response could be determined. In view of its good safety profile, sulfasalazine may be considered for systemic treatment of severe alopecia areata.

Background: Atopic dermatitis/eczema (AD/E) is a common disease. Few studies have attempted to quantify the cost to third-party payers., Objective: Our purpose was to identify the annual cost of medical services and prescription drugs for the treatment of AD/E to private insurance and Medicaid payers in the United States., Methods: We used a retrospective study design employing claims data from 1997 and 1998 from a private insurer and a state Medicaid program to analyze costs incurred. Beneficiaries were considered to have AD/E if they had at least one claim in 1997 with a primary or secondary listing of 1 of 3 diagnosis codes: 691.8, other atopic dermatitis and related conditions; 692.9, contact dermatitis and other eczema when no cause is specified; or 373.3, noninfectious dermatoses of eyelid. Patients who did not meet the diagnosis criteria served as a control group in each payer for comparisons of expenditures with the AD/E group., Results: Disease prevalence was 2.4% (private insurer) to 2.6% (Medicaid) of all eligible beneficiaries, and 3.5% to 4.1% of patients submitted at least one health care claim during the study period. Medicaid-insured patients used outpatient hospital visits and hospitalizations at a greater rate than did privately insured patients; neither used emergency departments extensively. The third-party payer cost of illness for AD/E ranged from $0.9 billion to $3.8 billion when projected across the total number of persons younger than 65 years insured by private insurers and Medicaid in the United States. More than one fourth of all health care costs for patients with AD/E may be attributed to AD/E and co-morbid conditions., Conclusions: Annual costs of AD/E are similar to those of other diseases such as emphysema, psoriasis, and epilepsy. Patients incur significant costs associated with AD/E and co-morbid conditions.

Background: Because health care resources are limited, therapeutic regimens should be assessed for their relative costs and effectiveness., Objective: We assessed cost-effectiveness for treating psoriasis using two strategies: one consisted principally of methotrexate and the other was principally a rotational schedule of modified cyclosporine (Neoral) with methotrexate., Methods: We performed a cost-effectiveness analysis using a computerized decision analytic model of simulated patients with moderate to severe psoriasis. Patients were randomly assigned to receive treatment with one of the two strategies. Direct costs included acquisition of medications, laboratory and physician fees, and costs of treating side effects. Because of uncertainty regarding rates of clearing of psoriasis, the relative efficacy of methotrexate and cyclosporine was varied over a wide range in a sensitivity analysis., Results: In the base case over a 10-year treatment period, the methotrexate strategy cost $33,000 and provided approximately 2 years clear of psoriasis compared with $38,000 and approximately 4 years clear of psoriasis for the rotational strategy. When the relative effectiveness of cyclosporine to methotrexate in clearing psoriasis varied from approximately 1 to 20, the rotational strategy cost from $4100 to $2700 per incremental clear year., Conclusion: In selecting therapies for psoriasis patients, both costs and effectiveness should be considered. In this simulation, patients could obtain additional periods clear of psoriasis at an incremental cost by using cyclosporine in rotation with methotrexate. If even a small utility gain accompanies the complete clearing of psoriasis, such a strategy may be a worthwhile investment of resources comparable to other healthcare interventions.

Cost-effectiveness studies are rising in importance as means for justifying expenditures on health interventions and as guides for making treatment and resource allocation decisions. However, the term "cost-effective" often is used erroneously, attributed to therapies that have not been subjected to rigorous cost analysis or comparison to an appropriate alternative. Health economic studies include cost-of-illness, cost-minimization, cost-effectiveness, cost-utility, and cost-benefit analyses. Each of these types of analyses differs in what it measures and under what circumstances its use is appropriate. This article describes the different types of economic studies, using examples to highlight their key features, and provides a summary of the key components of an economic analysis including perspective, cost and outcomes measurement, time horizon, cost-discounting, and sensitivity analysis.

Isotretinoin (13-cis-retinoic acid) is a retinoid that has been used over the past 2 decades to treat a wide variety of dermatologic conditions, some with great success. Although it is beneficial in many skin conditions, the side effects and toxicities of oral retinoids require careful monitoring by experienced physicians. The clinical applications of oral retinoids continue to expand both within and beyond the field of dermatology.

Three independent clinical studies were conducted in more than 1250 patients with moderate to moderately severe acne vulgaris to evaluate the efficacy and safety of a new combination gel that stably combines 5% benzoyl peroxide and 1% clindamycin. The results indicated that the benzoyl peroxide/clindamycin combination product was an effective treatment for reducing the inflammatory and noninflammatory lesions of acne vulgaris. In overall improvement as rated by the physicians and patients, the combination gel was superior to clindamycin alone, and in 2 of the 3 studies, to benzoyl peroxide alone. The antimicrobial activity of the combination gel was significantly (each P < .01) superior to that seen with topical application of its individual constituents, 5% benzoyl peroxide or 1% clindamycin, and was numerically better than that found with topical application of a 5% benzoyl peroxide/3% erythromycin combination product. As with benzoyl peroxide, dry skin was the most frequent side effect with use of the combination gel, with isolated incidences of other localized irritation. No other safety or tolerability concerns were identified.

Background: Topical clindamycin and benzoyl peroxide have each demonstrated clinical efficacy in the treatment of acne vulgaris. When used in combination, they promise greater efficacy than either individual agent used alone and the combined use of benzoyl peroxide with topical antibacterial has been shown to decrease the emergence of antibacterial resistant species., Objective: The objective was to determine the efficacy and safety of a combination benzoyl peroxide plus clindamycin in a gel formulation compared with each of its 2 active constituents in gel vehicle, and gel vehicle given alone in the treatment of acne vulgaris., Methods: In this 10-week, multicenter, double-blind trial, 480 patients with moderate to moderately severe acne were randomized to receive twice-daily treatment with 5% benzoyl peroxide plus 1% clindamycin, 5% benzoyl peroxide, 1% clindamycin, or vehicle., Results: Significantly greater reductions in the number of inflammatory and total lesions were demonstrated in patients using combination therapy compared with those using any of its 3 individual components. Likewise, both physicians' and patients' global evaluations showed significantly greater improvements with the combination therapy than with its individual components. The most frequent adverse effect, dry skin, occurred to a similar extent in the combination and benzoyl peroxide treatment groups., Conclusion: The improved efficacy obtained with the combination therapy was accompanied by a tolerability profile similar to that of benzoyl peroxide alone, making this new combination product an alternative antimicrobial therapy for acne vulgaris.

Background: Psoriasis is often treated with agents that activate nuclear hormone receptors for glucocorticoids, retinoids, and vitamin D. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a related nuclear hormone receptor that can be activated by its ligands, including the thiazolidinediones., Objective: To assess whether treatment with troglitazone, a currently available thiazolidinedione used to treat diabetes mellitus, has an effect on psoriasis in normoglycemic patients and whether ligands for PPARgamma have an effect on models of psoriasis., Design: Open-label administration of troglitazone in patients with psoriasis and evaluation of drug actions in cellular, organ, and transplant models of psoriasis., Setting: University and community hospital outpatient departments and university laboratories., Patients: Patients with chronic, stable plaque psoriasis and control subjects. Five patients with psoriasis received troglitazone (none withdrew); 10 different untreated patients and 10 controls provided tissue samples., Interventions: Oral troglitazone therapy at various dosages in patients with psoriasis; also, use of troglitazone, ciglitazone, and 15-deoxy-delta-12,14-prostaglandinJ2 in psoriasis models., Main Outcome Measures: Investigator-determined clinical results in patients and cell counts and histological evidence in models., Results: All patients' psoriasis improved substantially during troglitazone therapy. Peroxisome proliferator-activated receptor-gamma was expressed in human keratinocytes; ligands for PPARgamma inhibited the proliferation of normal and psoriatic human keratinocytes in culture. Troglitazone treatment normalized the histological features of psoriatic skin in organ culture and reduced the epidermal hyperplasia of psoriasis in the severe combined immunodeficient mouse and human skin transplant model of psoriasis (P<.05 compared with untreated controls)., Conclusions: Peroxisome proliferator-activated receptor-gamma might be a useful intracellular target for the treatment of psoriasis; further study is needed to assess the clinical value of ligands for PPARgamma, including troglitazone.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with abnormalities of both cellular and humoral immunity. Subcutaneous recombinant human interferon-gamma (IFN-gamma) provides therapeutic benefit to AD patients. In contrast to expectations, IFN-gamma does not cause a decrease in the elevated levels of circulating IgE levels in AD patients. We sought to determine cellular targets of IFN-gamma treatment that might explain its clinical benefit. Therefore, we evaluated blood leukocyte subsets by multiparameter flow cytometry in AD patients receiving IFN-gamma (n = 10) or placebo (n = 11) therapy compared to untreated normal volunteers (n = 14). Treated patients demonstrated reductions in WBC, eosinophil, and lymphocyte counts. Compared to normals, there was a reduced CD4/CD8 ratio in AD patients among activated, large mononuclear cells that was partially corrected with IFN-gamma treatment. Clinical improvement correlated with reductions in WBC (r = 0.9, P = 0.0003), eosinophil (r = 0.7, P = 0.035) and lymphocyte (r = 0.8, P = 0.013) counts, and with normalization of the CD4/CD8 ratio among large lymphocytes (r = 0.9, P = 0.04). The data indicate two potential modes of action for INF-gamma in AD. One mechanism represents normalization of selected immunologic abnormalities in AD; a second mechanism may be the modest reduction of circulating inflammatory cells. Adequacy of IFN-gamma therapy of AD may depend on bringing about these changes., (Copyright 1999 Academic Press.)

Background: Sirolimus (formerly rapamycin) is an immunosuppressive agent that interferes with T-cell activation. After 2 individuals with psoriasis developed a capillary leak syndrome following treatment with oral sirolimus lesional skin cells and activated peripheral blood cells were analyzed for induction of apoptosis., Observations: A keratome skin specimen from 1 patient with sirolimus-induced capillary leak syndrome had a 2.3-fold increase in percentage of apoptotic cells (to 48%) compared with an unaffected sirolimus-treated patient with psoriasis (21%). Activated peripheral blood T cells from patients with psoriasis tended to exhibit greater spontaneous or dexamethasone-induced apoptosis than did normal T cells, particularly in the presence of sirolimus., Conclusions: Severe adverse effects of sirolimus include fever, anemia, and capillary leak syndrome. These symptoms may be the result of drug-induced apoptosis of lesional leukocytes, especially activated T lymphocytes, and possibly release of inflammatory mediators. Because patients with severe psoriasis may develop capillary leak from various systemic therapies, clinical monitoring is advisable for patients with inflammatory diseases who are treated with immune modulators.

A multicentre study was conducted to compare clinical safety and efficacy of adapalene 0.1% solution and tretinoin 0.025% gel, both topical treatments for acne, in a once-daily dosage regimen for 12 weeks. A total of 297 patients were enrolled by eight investigators in this randomized, investigator-masked study in a parallel group design. An open label period using adapalene followed this study to assess the long-term safety of adapalene solution. Adapalene and tretinoin proved to be clinically and statistically effective in treating acne by reducing inflammatory (47% and 50%, respectively) and non-inflammatory lesions (57% and 54%) as compared to baseline. When comparing patients who had 75% or greater improvement in open comedones, adapalene was shown to be significantly more effective than tretinoin. No serious adverse event was reported during this study, including during the long-term period. The reactions that occurred were similar between treatments, i.e. burning, pruritus, scaling, dryness and erythema.

Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis., Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined., Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months., Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes., Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

Background: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of fungal infections., Objective: The purpose of this study was to assess the safety and efficacy of oral fluconazole 150, 300, and 450 mg administered once weekly compared with placebo in the treatment of distal subungual onychomycosis of the fingernail caused by dermatophytes., Methods: This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 349 patients with onychomycosis of the fingernails. Clinical and mycologic efficacy as well as measures of safety were assessed monthly for a maximum of 9 months of treatment, with additional safety visits occurring at weeks 2 and 6. For inclusion, patients were required to have clinically and mycologically documented onychomycosis of the fingernail caused by dermatophytes with at least 25% involvement of the target fingernail. After end of therapy, patients with improved or cured fingernails entered a blinded 6-month follow-up without drug treatment during which efficacy was assessed every 2 months. Efficacy was assessed by clinical (visual) and mycologic (microscopic and culture) measures. Clinical measures included assessments of the percentage of target nail involvement, measurement of the distance from the nail fold to the proximal onychomycotic border, and signs and symptoms of onychomycosis., Results: Fluconazole was significantly superior to placebo in eradicating clinical and mycologic symptoms of onychomycosis, both at the end of active treatment and at 6 months after treatment (p=0.0001 for all efficacy measures). At the end of therapy, 91% to 100% of patients in the fluconazole groups were judged clinical successes, defined as reduction of the affected area of the target nail to less than 25% or cure, compared with 8% for placebo. Clinical cure rates at end of therapy were 76%, 85%, and 90% for fluconazole 150, 300, and 450 mg, respectively, compared with 3% for placebo. These clinical success and cure rates were largely maintained or improved during follow-up. Clinical relapse in cured patients during the follow-up period was very low (1.5% to 3.3%). Fluconazole demonstrated mycologic eradication rates of 89% to 100% at the end of treatment and 90% to 99% at the end of follow-up; for placebo the rates were 8% and 12%, respectively., Conclusion: Fluconazole administered once weekly is safe and effective in eradicating distal subungual onychomycosis of the fingernail caused by dermatophytes.

Background: Tacrolimus is a potent immunosuppressant used in organ transplant recipients; an ointment formulation is being developed as a therapeutic agent for atopic dermatitis., Objective: Our purpose was to define the pharmacokinetics and evaluate tacrolimus 0.3% ointment as therapy for moderate to severe atopic dermatitis., Methods: Thirty-nine patients, 5 to 75 years of age, received 14 applications over 8 days. Serial blood samples were collected on days 1 and 8, with predose samples collected on days 2 through 7. Overall response and signs/symptoms were rated daily on days 1 through 11. Incidence of adverse events and laboratory profile were determined., Results: Mean area under the curve (0.9 to 42.5 ng x hr/ml) was highly variable and appeared to be related to size of application area. No systemic accumulation of tacrolimus was observed. Comparison to historical intravenous data indicates that absolute bioavailability of topical tacrolimus was less than 0.5%. Ninety-five percent of patients showed at least good improvement. All adverse events were transient. Burning was the most common application site adverse event and vasodilatation ("flushing/warmth") was the most common nonapplication site adverse event. No drug-related changes in laboratory profile were observed., Conclusion: The results of this study suggest that tacrolimus 0.3% ointment may be a safe and effective therapy for atopic dermatitis.

Two patients presented with the unusual condition of multiple warty dyskeratomas on the scalp. Biopsies of affected skin stained positive with human keratin monoclonal antibodies HKN-6 and -7, specific for cortex and inner root sheath of normal human hair, respectively. Multiple warty dyskeratomas are a rare occurrence and their aetiopathogenesis remains elusive. Positive immunohistochemical staining of a lesion with antikeratin antibodies HKN-6 and -7, specific for human hair keratin, suggests a follicular origin for warty dyskeratoma.

Background: Adapalene is a new chemical entity that exhibits tretinoin-like activities in the terminal differentiation process., Objective: We evaluated a dose range effect of two concentrations of adapalene gel as acne treatment and compared adapalene 0.1% gel with tretinoin 0.025% gel in the treatment of acne patients in two large multicenter studies., Methods: Multicenter, investigator-masked, parallel group studies including 89 acne patients in the dose range study and 591 patients in the concurrent controlled studies were conducted., Results: Adapalene gel 0.1% was significantly more effective in treating acne lesions than 0.03% adapalene gel. Adapalene gel 0.1% was significantly more effective than 0.025% or tretinoin gel in one study and of the same effectiveness in the other study. Adapalene gel was always better tolerated than tretinoin gel., Conclusion: Adapalene 0.1% gel is a safe and effective treatment of acne vulgaris.

Because the immunosuppressant rapamycin (sirolimus) blocks T cell proliferation in G1 phase, it has been proposed as a potential treatment for psoriasis, a skin disease characterized by T cell activation and keratinocyte stem cell hyperproliferation. To determine another potentially important mechanism through which rapamycin can act as an antipsoriatic agent, we tested its direct effect on keratinocyte stem cell proliferation in vitro as well as in vivo. In vivo cell cycle quiescent (G0 phase) stem cell keratinocytes in primary culture sequentially express de novo cyclin D1 and proliferating cell nuclear antigen (PCNA), prior to S phase entry, and upregulate beta1 integrin. Rapamycin inhibited the growth of keratinocytes that were leaving quiescence as well as those already in cell cycle without affecting cell viability. Although beta1 integrin(bright) expression was not affected, the number of beta1 integrin(bright) cells entering S/G2/M was significantly lowered by rapamycin. Cells treated with rapamycin exhibited decreased PCNA expression while cyclin D1 expression, which precedes PCNA expression in the cell cycle, was not affected. We found similar effects on stem cell keratinocytes in patients with psoriasis treated systemically with rapamycin. Because PCNA is required for cell cycle progression from G1 to S phase, our data indicate that inhibition of PCNA protein synthesis may be an important regulatory element in the ability of rapamycin to exert a G1 block.

Background and Design: Stretch marks are disfiguring lesions usually caused by excessive stretching of skin. We investigated the response of early, clinically active stretch marks to topical 0.1% tretinoin (retinoic acid) cream. In a double-blind, randomized, vehicle-controlled study, 22 patients applied either 0.1% tretinoin (n = 10) or vehicle (n = 12) daily for 6 months to the affected areas. Patients were evaluated by physical examination monthly and by analysis of biopsy specimens of stretch marks obtained before and at the end of therapy in comparison with untreated normal skin., Results: After 2 months, patients treated with tretinoin had significant improvements in severity scores of stretch marks compared with patients who received vehicle (P < .05). After 6 months, eight (80%) of the 10 tretinoin-treated patients had definite or marked improvement compared with one (8%) of the 12 vehicle-treated patients (P = .002). Targeted stretch marks in patients treated with tretinoin had a decrease in mean length and width of 14% and 8%, respectively, compared with an increase of 10% (P < .001) and 24% (P = .008), respectively, in patients who received vehicle. There were no significant differences in various measures of quality and quantity of dermal collagen and elastic fibers in stretch marks when tretinoin and vehicle treatments were compared., Conclusions: Topical application of tretinoin significantly improves the clinical appearance of early, active stretch marks. The processes that are responsible for the clinical improvement remain unknown.

Background: Adapalene is a new synthetic retinoid analogue developed for the topical treatment of acne vulgaris., Objective: The study was designed to compare the efficacy and safety and adapalene gel 0.1% with tretinoin gel 0.025% in the treatment of grade II to II facial acne vulgaris., Methods: Three hundred twenty-three patients were enrolled in this investigator-masked, randomized, parallel group, multicenter trial. Patients applied the test materials to the entire facial area daily, for a period of 12 weeks. Efficacy and cutaneous tolerance were assessed at baseline and weeks 2,4,8, and 12. Efficacy was determined by investigator counts of noninflammatory open and closed comedones, and inflammatory papules and pustules, as well as global improvement. Cutaneous tolerance was evaluated by erythema, scaling, and dryness, along with burning and pruritus., Results: Staring at weeks 2 and 4, adapalene gel produced numerically greater lesion reductions than did tretinoin gel for all lesion types. At week 12, the mean percent reduction in the different lesion counts was as follow: 49% versus 37% for total lesions (p<0.01); 46% versus 33% for noninflammatory lesions (p=0.02); 48% versus 38% for inflammatory lesions (p=0.06) in adapalene and tretinoin gel treatment groups, respectively. Cutaneous side effects were limited to a mild "retinoid dermatitis" occurring in both treatment groups; however, patients treated with adapalene gel tolerated this therapy significantly better than those treated with tretinoin gel. Laboratory test evaluations (hematology, blood chemistries, urinalysis) were performed in 54 patients before and after 3 months of treatment. No clinically significant changes were observed., Conclusion: Adapalene gel 0.1% applied once daily was significantly more effective in reducing acne lesions and was better tolerated than tretinoin gel 0.025% in the treatment of acne vulgaris.

Background and Design: The efficacy of topical tretinoin (all-trans-retinoic acid) in treating photoaging is well established. Questions that remain are (1) whether irritation causes all or part of the improvement; (2) the concentration of tretinoin that maximizes clinical response with minimal side effects; and (3) the effects of long-term treatment on components of the cutaneous immune system. To address these issues, 99 photoaged patients completed a 48-week study using 0.1% tretinoin cream (n = 32), 0.025% tretinoin (n = 35), or vehicle (n = 32) once daily in a double-blind manner. Before and after treatment, we assessed histologic features, keratinocyte expression of HLA-DR and intercellular adhesion molecule-1, numbers of epidermal Langerhans' cells and epidermal and dermal T lymphocytes, and vascularity as measured by dermal endothelial cell area., Results: Both 0.1% and 0.025% tretinoin produced statistically significant overall improvement in photoaging of the face compared with vehicle; there were no clinically or statistically significant differences in efficacy between the two concentrations of tretinoin. After 48 weeks, 0.1% and 0.025% tretinoin produced similar statistically significant epidermal thickening (by 30% and 28%, respectively) compared with vehicle (11% decrease) and increased vascularity (by 100% and 89%, respectively) compared with vehicle (9% decrease). By various analyses, irritant side effects (erythema and scaling) were statistically significantly greater with 0.1% tretinoin than with 0.025% tretinoin. No significant changes occurred in any immunologic markers when tretinoin and vehicle treatments were compared., Conclusions: Tretinoin 0.1% and 0.025% produce similar clinical and histologic changes in patients with photoaging, despite significantly greater incidence of irritation with the higher concentration. The separation between clinical improvement and irritation suggests that mechanisms other than irritation dominate tretinoin-induced repair of photoaging in humans.

Background: Cyclosporine therapy is highly effective in the treatment of psoriasis. To minimize side effects, the lowest effective dosage for maintenance therapy should be sought., Methods: We selected 61 patients who had achieved clearing or near-clearing of psoriasis during an induction phase of cyclosporine therapy. We then randomly assigned them in a double-blind fashion to receive one of two dosages of cyclosporine (1.5 or 3 mg/kg per day) or placebo for maintenance treatment. For each patient, the time to relapse was the time from the start of maintenance therapy until the patient showed a two-point worsening of psoriasis on a seven-point scale, up to a maximum of 4 months, when the study ended., Results: Sixty patients completed the maintenance study. The mean time to relapse was significantly longer in the 3-mg/kg group (12 +/- 1 weeks) than in the 1.5-mg/kg group (9 +/- 1 weeks; P = .04) and the placebo group (7 +/- 1 weeks; P = .002); the latter two groups were not significantly different (P = .3). When the study ended, 57% of the 3-mg/kg group had not relapsed, compared with 21% and 5% of the 1.5-mg/kg and placebo groups, respectively. The following factors were associated with longer remissions: less psoriasis at the start of maintenance dosing (r = .40, P = .002); lower dosage of cyclosporine to achieve clearing or near-clearing during induction (r = -.30, P = .02); higher maintenance dosing (r = .38, P = .004); and smaller differences between the induction and maintenance dosages (r = -.41, P = .002). Patients' laboratory values improved compared with those at induction, and no patient experienced important clinical side effects during maintenance dosing., Conclusions: After clearing or near-clearing is achieved in patients with severe psoriasis, 3 mg/kg per day is a reasonable dosage to choose for maintenance. Patients who are more responsive to cyclosporine (as measured by greater clearing of psoriasis at lower induction dosages) tend to have longer remissions.

Background: Etretinate is an aromatic retinoid given orally to treat severe psoriasis, a chronic disease that often requires long-term therapy., Objective: We assessed the safety of long-term therapy with etretinate for psoriasis., Methods: This 5-year prospective study of a cohort of 956 patients with psoriasis treated with etretinate assessed the frequency of adverse events in relation to total use and in relation to the frequency of these events in control populations., Results: Our data do not provide evidence for an increased risk of cardiovascular disease, cancer, diabetes, or inflammatory bowel disease in association with long-term etretinate use. Although some patients reported that joint problems improved with the use of etretinate, a greater number associated the use of etretinate with joint problems., Conclusion: With proper patient selection and monitoring, long-term etretinate therapy (up to 4 years) does not appear to be accompanied by a substantial increased risk of major adverse effects.

Objective: Psoriatic arthritis (PsA) is often poorly responsive to 2nd line antirheumatic drug therapy. Sulfasalazine has recently gained wide acceptance in the treatment of rheumatoid arthritis, and beneficial effects have also been noted in ankylosing spondylitis and reactive arthritis. We report a double blind placebo controlled study of sulfasalazine in PsA., Methods: Twenty-four patients with active PsA were randomized to receive either sulfasalazine (3 g/day) (n = 10) or placebo (n = 14) for 8 weeks, in a double blind manner, followed by an 8 week open label crossover phase for nonresponding placebo patients., Results: Compared with placebo controls, sulfasalazine treated patients were significantly improved at Weeks 4 and 8 with respect to physician (p < 0.01) and patient (p < 0.05) global assessments. Duration of morning stiffness was significantly decreased at Week 8 (p < 0.01). Clinical variables of disease activity returned to baseline after a 4 week drug washout period in 5 evaluable patients. Six patients in the placebo group crossed over to an 8 week open label phase and demonstrated significant improvements in joint scores, 50 ft walking time, and global patient assessment. Sulfasalazine treated patients also showed significant improvements in cutaneous involvement., Conclusion: Sulfasalazine was effective in PsA, with efficacy observed as early as the 4th week of treatment. Longterm studies are needed to determine whether such therapy can modify disease outcome.

The impact of long-term cyclosporin therapy on kidney structure and function was evaluated in psoriasis patients with normal baseline renal function. Patients received cyclosporin at an average dose 3.9 mg/kg/day for up to three years and underwent serial kidney biopsies and measurements of iothalamate clearance and serum creatinine concentration. Kidney biopsy specimens (assessed on a scale of 0 to 4 where 0 = normal and 4 = severe) from 19 cyclosporin-treated patients as compared to 38 age-matched transplant donors showed increased interstitial fibrosis (1.9 +/- 0.2 vs. 0.3 +/- 0.1, P < 0.0001) and tubular atrophy (1.6 +/- 0.2 vs. 0.3 +/- 0.1, P < 0.0001) at one year. Eleven patients had a second biopsy after an additional two years of cyclosporin treatment demonstrating additional interstitial fibrosis (1.8 +/- 0.2 to 2.4 +/- 0.3, P = 0.002) and tubular atrophy (1.4 +/- 0.2 to 1.9 +/- 0.2, P = 0.053), and the onset of cyclosporin-associated arteriolopathy (0 to 0.5 +/- 0.2, P = 0.02). Quantitative digital morphometric analysis of trichrome-stained specimens also showed increased interstitial fibrosis (22.5 +/- 1.5 to 32.0 +/- 2.0% of interstitial area, P = 0.0008). Iothalamate clearance declined at an average rate of -3.1 ml/min/1.73 m2 per year (95% CI -5.8, -0.3) during the period of cyclosporin treatment. The slope of reciprocal serum creatinine declined by -0.06 dl/mg per year (95% CI -0.08, -0.04). Chronic cyclosporin treatment of otherwise healthy psoriasis patients is associated with progressive renal structural injury and reduced glomerular filtration rate.

Background: The psychosocial aspects of the treatment of photodamaged skin have received little attention., Objective: We prospectively examined the psychosocial correlates of the treatment of mildly to severely photodamaged skin., Design: Sixty subjects (age, 53.3 +/- 1.3 years [mean +/- standard error]; 35 receiving retinoic acid and 25 the inactive vehicle) completed a battery of psychosocial ratings before starting therapy and after 24 weeks of therapy with retinoic acid or vehicle., Results: Before therapy, the subjects had pathologically high obsessive-compulsiveness scores (measured by the Brief Symptom Inventory [BSI]). From before to after therapy, the retinoic acid group reported decreased obsessive-compulsiveness (BSI) (p = 0.01), and decreased phobic anxiety (BSI) (p = 0.04), whereas the vehicle group reported an increase (p < 0.05) in both these symptom dimensions., Conclusion: High obsessive-compulsiveness (BSI), which is associated with excessive perfectionism and need for control, probably predisposed the subjects to seek treatment of their wrinkles. In the retinoic acid group but not the vehicle group there was an improvement in obsessive-compulsiveness and decreased anxiety in previously anxiety-provoking situations.

Background and Design: Melasma is an acquired, masklike, facial hyperpigmentation. The pathogenesis and treatment of melasma in black (African-American) patients is poorly understood. We investigated the efficacy of topical 0.1% all-trans-retinoic acid (tretinoin) in the treatment of melasma in black patients. Twenty-eight of 30 black patients with melasma completed a 10-month, randomized, vehicle-controlled clinical trial in which they applied either 0.1% tretinoin or vehicle cream daily to the entire face. They were evaluated clinically (using our Melasma Area and Severity Index), colorimetrically, and histologically., Results: After 40 weeks, there was a 32% improvement in the Melasma Area and Severity Index score in the tretinoin treatment group compared with a 10% improvement in the vehicle group. Colorimetric measurements showed lightening of melasma after 40 weeks of tretinoin treatment vs vehicle. Lightening of melasma, as determined clinically, correlated well with colorimetric measurements. Histologic examination of involved skin revealed a significant decrease in epidermal pigmentation in the tretinoin group compared with the vehicle group. Side effects were limited to a mild "retinoid dermatitis" occurring in 67% of tretinoin-treated patients. Among the patients in this study in comparison with comparably recruited white patients, melasma was reported to have begun at a later age and was more likely to be in a malar distribution., Conclusions: This controlled study demonstrates that topical 0.1% tretinoin lightens melasma in black patients, with only mild side effects.

Background: Hyperpigmented lesions are a predominant component of photoaging in Chinese and Japanese persons. Topical 0.1% tretinoin cream improves the hyperpigmentation associated with photoaging in Caucasian persons., Objective: Our purpose was to assess the efficacy of 0.1% tretinoin cream treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients., Methods: Forty-five photoaged patients (23 Chinese, 22 Japanese) completed a double-blind, randomized study in which 21 applied 0.1% tretinoin cream and 24 applied vehicle cream once daily to face and/or hands for 40 weeks. Patients' hyperpigmented lesions were evaluated clinically and by colorimetry throughout the study and by histologic analysis of skin biopsy specimens taken before therapy and at the end of treatment., Results: At the end of treatment, hyperpigmented lesions of the face and hands were lighter or much lighter in 90% of patients receiving tretinoin compared with 33% receiving vehicle (p < 0.0001). Colorimetry demonstrated significant lightening of lesions after tretinoin compared with vehicle (p < 0.05). Histologic analysis of hyperpigmented lesions demonstrated a statistically significant 41% decrease in epidermal pigmentation with tretinoin therapy as compared with a 37% increase in the vehicle group (p = 0.0004). No patient withdrew for adverse effects., Conclusion: By clinical, colorimetric, and histologic evaluation, 0.1% tretinoin cream significantly lightens the hyperpigmentation of photoaging in Chinese and Japanese patients.

Pruritus, or itching, is the most common symptom of dermatologic disease. Psychologic factors can affect pruritus, and in an earlier study of inpatients with moderate to severe psoriasis, we observed that the degree of depressive psychopathology directly correlated with pruritus severity. In this study we investigated the relation between pruritus and depression among a group of patients (N = 252) with a wide range of pruritic skin disorders, including outpatients with mild to moderate psoriasis (N = 77), atopic dermatitis (N = 143) and chronic idiopathic urticaria (N = 32). All patients self-rated the severity of their pruritus on a 10-point scale and completed a battery of psychologic ratings, including the Carroll Rating Scale for Depression (CRSD). We observed a direct correlation (Pearson's r = .34, p < .0001) between pruritus severity and the CRSD score. The correlations between pruritus severity and CRSD scores for each individual diagnostic group were as follows: psoriasis: Pearson's r = .32, p = .004; atopic dermatitis: Pearson's r = .21, p = .013; and chronic idiopathic urticaria: Pearson's r = .34, p = .06. When the subjects with pruritus scores less than 5.5 were compared with subjects with pruritus scores greater than 5.5, significant differences (p < .05) in depression scores were found for all three dermatoses by the Mann-Whitney U test. The depressed clinical state may reduce the threshold for pruritus.

To better understand the cellular target(s) of cyclosporin action in psoriasis, we have studied the effects of systemic short-term (7 d), low-dose (3-7.5 mg/kg) cyclosporin A administration on the expression of the cytokines interleukin (IL)-8 and IL-1 beta in psoriatic lesions. RNA blot hybridization analysis of pretreatment keratome biopsies revealed that expression of both cytokine mRNAs was highly variable from patient to patient. Significant covariation of both cytokine mRNA levels was noted (r = 0.86, p < 0.0001). However, there was no significant correlation between expression of either cytokine and clinical severity, as measured by the pretreatment Psoriasis Area and Severity Index (PASI). IL-1 beta protein levels measured by enzyme-linked immunosorbent assay (ELISA) were highly correlated with IL-1 beta mRNA levels, indicating that the differences in transcript levels accurately reflect differences in epidermal cytokine protein. Significant reductions in both cytokine transcripts and in IL-1 beta immunoreactive protein were noted in the high expression subgroup after 1 week of cyclosporin A therapy, prior to detectable clinical improvement. In contrast to its pronounced effects on epidermal cytokine expression in vivo and the allogeneic mixed lymphocyte reaction in vitro, cyclosporine A did not inhibit the induction of intercellular adhesion molecule (ICAM)-1 or IL-8 mRNAs by cultured keratinocytes in response to IL-1 beta or the combination of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. These data suggest that epidermal keratinocytes respond to signals produced by activated T cells by coordinate expression of multiple cytokines, and that cyclosporin A acts primarily through blockade of T cells, rather than through keratinocyte activation.

Melasma is a common disorder of cutaneous hyperpigmentation predominantly affecting the faces of women. Little is known about the aetiology of melasma, and treatment is frequently disappointing. Topical tretinoin is of benefit in treating other forms of hyperpigmentation, for example liver spots, and we therefore investigated its effectiveness in melasma. Thirty-eight women completed a randomized, vehicle-controlled study, in which they applied 0.1% tretinoin (n = 19) or vehicle cream (n = 19) once daily to the face for 40 weeks. At the end of treatment 13 (68%) of 19 tretinoin-treated patients were clinically rated as improved or much improved, compared with 1 (5%) of 19 in the vehicle group (P = 0.0006). Significant improvement first occurred after 24 weeks of tretinoin treatment. Colorimetry (an objective measure of skin colour) demonstrated a 0.9 unit lightening of tretinoin-treated melasma and a 0.3 unit darkening with vehicle (P = 0.01); these results correlated with clinical lightening (r = 0.55, P = 0.0005). Histologically, epidermal pigment was reduced 36% following tretinoin treatment, compared with a 50% increase with vehicle (P = 0.002). Reduction in epidermal pigment also correlated with clinical lightening (r = -0.41, P = 0.01). Moderate cutaneous side-effects of erythema and desquamation occurred in 88% of tretinoin-treated and 29% of vehicle-treated patients. Topical 0.1% tretinoin produces significant clinical improvement of melasma, mainly due to reduction in epidermal pigment, but improvement is slow.

Background: Substance P, an undecapeptide neurotransmitter, has been implicated in the pathophysiology of psoriasis and pruritus., Objective: Safety and efficacy of topical capsaicin, a potent substance P depletor, were evaluated in patients with pruritic psoriasis., Methods: Patients applied capsaicin 0.025% cream (n = 98) or vehicle (n = 99) four times a day for 6 weeks in this double-blind study. Efficacy was based on a physician's global evaluation and a combined psoriasis severity score including scaling, thickness, erythema, and pruritus., Results: Capsaicin-treated patients demonstrated significantly greater improvement in global evaluation (p = 0.024 after 4 weeks and p = 0.030 after 6 weeks) and in pruritus relief (p = 0.002 and p = 0.060, respectively), as well as a significantly greater reduction in combined psoriasis severity scores (p = 0.030 and p = 0.036, respectively). The most frequently reported side effect in both treatment groups was a transient burning sensation at application sites., Conclusion: Topically applied capsaicin effectively treats pruritic psoriasis, a finding that supports a role for substance P in this disorder.